Glaucoma is the second leading cause of unrecoverable blindness, and globally there are about 5 million patients who had lost their vision due to glaucoma, which are about 12.3% of global blindness (Foster and Resnikoff, 2005; and Resnikoff et al., 2002). Glaucoma is not a single disease, but rather represents a group of diseases of various patterns that show diverse clinical and histopathologic manifestations, such as certain changes in the optic disc and damages to RGCs with resultant visual field loss. Although there are other various diseases besides glaucoma that lead to RGC injury, selective and progressive death of RGCs is a distinctive feature of glaucoma (Osborne et al. 1999; Kaushik et al., 2003; and Kuehn et al., 2005). Therefore, a major goal of glaucoma therapy is to prevent the death of RGCs.
It is a well-known fact that a rise of IntraOcular Pressure (IOP) is the most definite risk factor among others associated with glaucoma, and lowering the IOP to an appropriate level can slow the progression of glaucoma (Chauhan and Drance, 1992; Dielemans et al., 1994; Collaborative Normal-Tension Glaucoma Study Group, 1998a, 1998b; Heijl et al., 2002; and Maier et al., 2005). Based on this fact, glaucoma studies in the last several decades have focused on lowering the IOP. However, it has been reported that glaucomatous damage can continue in some patients even after the IOP has been lowered to a proper level, and this phenomenon was observed even in some glaucoma patients whose IOP is within the normal range (Werner and Drance, 1977). These facts imply that there are another mechanisms related to the development and progression of glaucoma, in addition to the elevation of IOP. Therefore, many glaucoma studies have attempted to find other mechanisms that cause selective RGC apoptosis, which is the most crucial pathophysiologic feature of glaucoma. It was found that hematological factors (e.g., loss of autoregulation in ocular perfusion pressure and hypoxia resulted therefrom, ischemia, ischemic-reperfusion, etc.) are associated with glaucomatous damage (Chung et al., 1999; Cioffi and Wang, 1999; Flammer, 1994; Flammer et al., 2002; and Luo et al., 2001). Recent glaucoma studies have focused to identify neuroprotective effects in prevention of RGC apoptosis (Garcia-Valenzuela et al., 1995; Gross et al., 1999; Quigley et al., 1995; Kerrigan et al., 1997; Okisaka et al., 1997; and Kuehn et al., 2005).
It is well-known that TNF-α, which is a proinflammatory cytokine that is synthesized and released from astrocytes and microglia in the Central Nervous System (CNS), is implicated in cytotoxicity in several neurodegenerative diseases including multiple sclerosis, Parkinson's disease, and Alzheimer's disease (Moreau et al., 1996; Tarkowski et al., 2003; and Sawada et al., 2006). Such cell cytotoxicity of TNF-α is caused by cell apoptosis induction through TNF Receptor-1 (TNF-R1) (Hsu et al., 1995). It is reported that TNF-α is also associated with retinal damage or optic nerve damage in retinal tissue induced by ischemia (Fontaine et al., 2002; Gardiner et al., 2005; Koizumi et al., 2003; and Yoshida et al., 2004). This implies that TNF-α induced neuro-retinal apoptosis is involved in pathologic damage due to a mechanism related to ischemic retinopathy and ischemic neuropathy. Moreover, the fact that TNF-α induced by optic nerve damage from axotomy or crushing damage is the cause of RGC death means that TNF-α is associated with neuro-retinal injury by traumatic optic neuropathy as well (Diem et al., 2001; and Tezel et al., 2004). It is also known that TNF-α is involved in AIDS-related optic neuropathy (Lin et al., 1997).
Particularly, it is reported that TNF-α and its receptor TNF-R1 are upregulated in patients with glaucoma. TNF-α is upregulated in glial cells of glaucoma patients and TNF-R1 is upregulated in RGCs (Tezel et al., 2001). Microgliacytes and astrocytes of glaucomatous optic nerve heads contain abundant TNF-α (Yan et al., 2000; Yuan and Neufeld, 2000, 2001). In an in vitro glaucoma experimental model of ischemia or with an elevated hydrostatic pressure, TNF-α production is increased in glial cells, which induces apoptosis in RGCs (Agar et al., 2006; and Tezel et al., 2000). A similar result may also be obtained in an in vivo glaucoma animal test that intravitreal injection of TNF-α induces axonal degeneration and delayed loss of RGC cell bodies (Kitaoka et al., 2006). Intravitreal injection of TNF-α to rabbit eyes induces degeneration of optic nerves (Madigan et al., 1996). Until now, there has been no evidence that TNF-α directly contributes to RGC death, but it is considered that, according to previous reports, TNF-α would play a critical role in the pathogenesis of RGC apoptosis in glaucomatous eyes.
From the late 1990's, researchers have been actively seeking for drugs having neuroprotective effects against RGC death due to glaucoma. It is reported that calcium channel blockers (Kitazawa et al., 1989; Netland et al., 1993; Bose et al., 1995; and Sawada et al., 1996), neurotrophines (Johnson et al., 1986; Mansour-Robaey et al., 1994; Weibel et al., 1995; Di Polo et al., 1998; Pease et al., 2000; Quigley et al., 2000; Ko et al., 2001; Martin et al., 2003; and Ji et al., 2004), α2-adrenergic agonists (Donello et al., 2001; Lafuente et al., 2001, 2002; WoldeMussie et al., 2001; Aviles-Trigueros et al., 2003; and Wheeler et al., 2003), N-Methyl-D-Aspartate (NMDA) receptor antagonists (Vorwerk et al., 1996; and Hare et al., 2004a, b), Nitric Oxide Synthase (NOS) inhibitors (Neufeld et al., 2002), and other materials (Chaudhary et al., 1999; Kipnis et al., 2000; Schori et al., 2001; Quaranta et al., 2003; Hirooka et al., 2004; Qin et al., 2004; and Lingor et al., 2005) have neuroprotective effects on RGCs. However, an accurate mechanism for RGC apoptosis induced by glaucoma is not yet known, and an effective neuroprotective drug for the inhibition of apoptosis of RGCs has not been developed to date.